The purpose of this proposal is to generate new and useful information on the role of products of lipoxygenase-mediated arachidonic acid metabolism as endogenous mediators of edema formation in acute lung injury (ALI). It was demonstrated previously in an animal model of ALI produced by intravenous ethchlorvynol (ECV) administration that cyclooxygenase metabolites influence the development of systemic hypoxemia, but not the accumulation of extravascular lung water (EVLW). In this model a product of lipoxygenase activity, leukotriene C4 (LTC4) was present in increased amounts in edema fluid and bronchopulmonary lavage fluid (BALF). In preliminary studies in which ALI was produced by phorbol myristate acetate (PMA), LTC4 and LTD4 were found to be increased in BALF. These studies, coupled with the finding that LTC4 was increased in humans with the adult respiratory distress syndrome, suggest that LTC4 and LTD4, two edemagenic products of lipoxygenase metabolism, may play a role in the edema of ALI. The Specific Aims of this proposal are: 1) to demonstrate that increased production of LTC4 and LTD4 is a feature common to two dissimilar models of ALI; 2) to establish that the increased production of LTC4 and LTD4 occurs in and is confined to the injured ling; 3) to demonstrate that increased production of LTC4 and LTD4 is specific for ALI, i.e., LTC4 and LTD4 are not produced in association with hydrostatic pulmonary edema; 4) to establish that products of cyclooxygenase activity are not responsible for the edema of ECV- and PMA-induced ALI; and 5) to establish that LTC4 and LTD4 contribute to the formation of nonhydrostatic pulmonary edema in these models of ALI. Experiments will be performed in which either unilateral or bilateral ALI is produced in dogs. Concentrations of LTC4 and LTD4 will be determined in blood, edema fluid, BALF and lung slice incubation medium. Attempts will be made to correlate the concentrations of LTC4 and LTD4 to the extent of edema formation. The role of LTC4 and LTD4 as factors contributing directly to edema formation will be investigated through the use of synthesis inhibitors and a leukotriene receptor antagonist. Successful completion of these studies will make the mechanisms of edema formation more comprehensible to the basic scientist and will permit the clinician to formulate more rational therapeutic approaches to the clinical condition.